Project Summary/Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated basic-helix-loop-helix-PAS transcription factor. This receptor is responsible for our bodily response to exposure of environmental pollutants such as polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and dioxins. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most studied and best known ligand of AHR. Expression of AHR is up-regulated in human cancers and during T cell differentiation. Malfunction of the events affecting the ahr gene expression would undoubtedly cause problems in cancer, aberrant immune response, stem cell development, and our response to toxic environmental chemicals. However, our knowledge of how the AHR protein levels are maintained without ligand treatment is very limited. Our data suggested a strong likelihood that autophagy is responsible for the AHR protein degradation in human cells. In this grant proposal, we will investigate whether and how autophagy regulates the AHR protein levels in human cells. In brief, we will perform experiments to study the following aims: (1) we will determine whether the autophagy-mediated AHR protein degradation occurs in cancerous and normal human cells (Aim 1); we will determine the autophagy mechanism that is involved in the AHR degradation (Aim 2) and (3) we will investigate how triple-negative human breast cancer cells are more sensitive in the autophagy- mediated AHR protein degradation when compared to non-triple-negative breast cancer cells (Aim 3).